Barbituric acid compositions



Patented Sept. 24, 1946 UNITED STATES PATENT orrlcs BARBITURIC ACID COMPOSITIONS Milton '1. Bush, Nashville, Tenn., assi'gnor to Mallinckrodt. Chemical Works, St. Louis, Mo., a corporation of Missouri No Drawing. Application July 17, 1942, Serial No. 451,311

4' Claims.

This invention relates to barbituric acid compositions, and more particularlyto non-aqueous solutions of barbituric acids suitable for parenterai administration.

Among the objects of this invention are the provisionv of barbituric acid solutions of the type indicated which are stable, non-alkaline and nonirritating; the provision of barbituric acidsolutions which. may be. utilized for intramuscular injections; and the provision of stable barbituric acid solutions which may be administered orally or intravenously, as well as intramuscularly. Other objectswill be in part obvious and in part pointed out hereinafter.

The invention accordingly comprises the ingredients and combinations of ingredients, the proportions thereof, and features of composition, which will be exemplified in the products hereinafter described, and the scope of the application of which will be indicated in the following claims.

Barbituric acids are useful as hypnotics and anaesthetics. When administered by injection they are customarily employed in the form of strongly alkaline aqueous solutions of their sodium or other salts. These solutions are generally unstable, must be prepared fresh from previously sterilized components and decompose rapidly on heating- Moreover, they are very irritating to human tissue due both to their alkalinity and the osmotic effect that such hypertonic solutions produce and consequently their use is strictly limited to oral or intravenous administration.

In many instances it is impossible to administer these barbituric acids either orally or intravenously. For example, where the patient is suffering from shock, or where there is little time to carry out the operation, it may be difficult to find the patients veins. The veins collapse in shock and are, therefore, difficult to locate, while if the administration is to be carried out on a battlefield or under other difficult conditions, it may likewise be hard to quickly determine the position of the patients veins. It may be impossible to attempt oral administration due to the failure of the patient to cooperate or to many.

other conditions. On the other hand, the intramuscular route is always available and it would be possible to utilize these barbituric acids ifsolutions suitable for intramuscular injection were obtainable.

According to the present invention, solutions of the barbituric acids are provided. These solutions can be injected intramuscularly without detrimental effect upon the patient, producing 2 the desired hypnosis or anaesthesia without irritation. They can be sterilized and kept for long periods of time without loss of activity.

The solutions of the present invention comprise barbituric acids dissolved in a non-aqueous sol vent. The organic solvents employed must act as such for the barbituric acid. or acids utilized; thatis, the barbituric acids must be soluble to produce the required concentration of hypnotic or anaesthetic component in the organic solvent; The solubility of the barbituric acid in the organic solvent must not be substantially less than 10% and preferably is at least The-re isno upper limit for thi solubility.

Moreover, the solvent itself must not be too soluble in or be miscible with water. Solubilities of the organic solvents in water of the order of 10% are, for example, satisfactory, and may be even higher without unduly detracting from the effectiveness of the barbituric acid. Zero is the lower limit for this solubility.

If the solvent possesses too great a solubility in water the effectiveness of the resulting barbituric acid composition is markedly decreased. Solubilities as high as 15% of the organic solvent in water are permissible. The preferred type of solvent, however, has a solubility in water of approximately 10% or less.

Typical of the solvents which may be employed are paraldehyde, triacetin, and olive oil, although other organic solvents possessing the requisite low solubility in water and having a pH value in aqueous solution of substantially 7 may a be substituted. 1

A wide range of barbituric acids may be utilized. as the active hypnotic or anaesthetic agent in the instant compositions. For example:

1-methyl-5-allyl-5-isopropyl 5-ethyl-5-n-butyl K 5-.allyl-5-isopropyl 5-ethyl-5 -sec-butyl 5-ethyl-5 l-methylbutyl) 1 -methyl-5-ethyl-5- l-methylbutyl) 5-allyl-5- l -methylbutyl) Barbituric acids have been utilized either alone or in combination with each other or with other hypnotics. All of the compositions listed above possess sufficient solubility in paraldehyde and triacetin, for example, to enable the injection intramuscularly of effective hypnotic and/0r anaesthetic doses without the utilization of detrimentally large quantities of solution.

In general it is desirable to inject only a small volume of solution so the solubility and necessary dosage will usually as a practical matter de,

the present invention in concentrations of the order of, for example, 250 mg./m1. are very close to the corresponding doses required of the customarily employed 10% aqueous solutions of the sodium salt of the corresponding barbituric acid.

The organic solvent employed must not itself be toxic or irritating to human beings. Paraldehyde is an instance of a solvent which is not toxic and has even been employed as a hypnotic. However, its hypnotic activity is only a fraction (about & or a,) that of allyl-(l-methylbutyl) barbituric acid, for example, so that this solvent plays only a negligible part in the activity of such a solution. A 30% solution of allyl-(lmethylbutyl) bar-bituric acid in paraldehyde is stable. This is true even when such a solution is heated to 120 C. for as long as four hours. Such stability makes it possible to sterilize the solution with heat.

Although the barbituric acid solutions of the present invention are of especial value for intramuscular injection, they may also be injected intravenously. If such an injection is made with the usual slowness, no detrimental symptoms are encountered.

As indicated above, two or more of the barbituric acids may be used in the same solution or one or more of such acids may be used in a solution with another narcotic, hynotic or anaesthetic, such as morphine, dilaudid, etc.

In view of the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.

As many changes could be made in the above products without departing from the scope of the invention, it is intended that all matter con- 'tained in the above description shall be interpreted as illustrative and not in a limiting sense.

I claim:

1. A hypnotic composition for intramuscular injection comprising a solution of a barbituric acid in paraldehyde.

2. A hypnotic composition for intramuscular injection comprising a solution of 5-allyl-5-(lmethylbutyl) barbituric acid in paraldehyde.

3. A hypnotic composition for intramuscular injection comprising a solution of 1-methyl-5- ally1-5-isopropyl barbituric acid in paraldehyde. 4. A hypnotic composition for intramuscular injection comprising a solution of N-methyl-5- ethy1-5-(1-methylbuty1) barbituric acid in paraldehyde.

MILTON T. BUSH. 

